Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause significant economic loss worldwide and remains a serious threat to the pork industry.Currently,vaccination strategies provide limited protection against PRRSV infection,and consequently,new antiviral strategies are urgently required.Andrographolide (Andro) and its derivative potassium dehydrographolide succinate (PDS) have been used clinically in China and other Asian countries as therapies for inflammation-related diseases,including bacterial and viral infections,for decades.Here,we demonstrate that Andro and PDS exhibit robust activity against PRRSV replication in Marc-145 cells and primary porcine alveolar macrophages(PAMs).The two compounds exhibited broad-spectrum inhibitory activities in vitro against clinically circulating type 2 PRRSV GD-HD,XH-GD,and NADC30-1ike HNhx strains in China.The EC50 values of Andro against three tested PRRSV strain infections in Marc-145 cells ranged from 11.7 to 15.3 μmol/L,with selectivity indexes ranging from 8.3 to 10.8,while the EC50 values of PDS ranged from 57.1 to 85.4 μmol/L,with selectivity indexes ranging from 344 to 515.Mechanistically,the anti-PRRSV activity of the two compounds is closely associated with their potent suppression on NF-κB activation and enhanced oxidative stress induced by PRRSV infection.Further mechanistic investigations revealed that PDS,but not Andro,is able to directly interact with PRRSV particles.Taken together,our findings suggest that Andro and PDS are promising PRRSV inhibitors in vitro and deserves further in vivo studies in swine.